CD30, a marker to detect the high-risk kidney transplant recipients.

BACKGROUND: Sensitization of potential renal transplant recipients may impact the selection of donors and the outcome of transplant. Another element of the potential kidney transplant recipient immune system that provides useful information regarding the transplant outcome is the immunologic CD30 molecule. METHODS AND RESULTS: This study shows a significant correlation between the pre-transplant high level of soluble CD30 and increased incidence of post-transplant infection. Only 7/34 (20.6%) of the patients who had a low level of sCD30 (< 90 U/mL) developed infection as compared with the 25/58 (43.1%) of the patients who had a high level (> 90 U/mL) of sCD30 (p < 0.04). Higher level of sCD30 pre-transplant was also correlated with the increased level of serum creatinine (p < 0.05) and pre-transplant malignancy (p < 0.04). A significant higher level of sCD30 was also noted among females (74%), as compared with males (50%) with p < 0.03. In addition, significant effect of 3-6 human leukocyte antigen (HLA) mismatches on rejection was seen. CONCLUSIONS: These results show that higher pre-transplant immunologic reactivity measured by sCD30 level was associated with post-transplant outcome. The high level of sCD30 among females may indicate an active immunologic status, perhaps because of previous pregnancies.

Pre-transplant level of soluble CD30 is associated with infection after heart transplantation.

BACKGROUND: One immunologic element of the immune system is the CD30 molecule which belongs to the TNF-R superfamily. CD30 can serve as a T-cell signal transducing molecule and is expressed by a subset of activated T lymphocytes, CD45RO(+) memory T cells. Augmentation of soluble CD30 during kidney transplant (Tx) rejection has been reported. Our study was to determine if the level of sCD30 prior to heart transplant (HTx) could categorize the patients (pts) into high or low immunologic risk for post-Tx outcome. METHODS: Pre-Tx sera from 100 consecutive HTx recipients were studied. sCD30 was detected by ELISA using the commercially available CD30 monoclonal antibody. Level of sCD30 was correlated with two-yr Tx outcome. RESULTS: Significant correlation was seen between the high level of sCD30 and lower incidence of infection. Four of the 35 pts with pre-Tx high level of sCD30 level (>90 U/mL) developed infection post-Tx. However, 31/65 pts who had a low level of sCD30 (<90 U/mL) developed infection post-transplantation (p < 0.0003). No remarkable differences were noted with the other clinical parameters, including mean hospitalization, 3A biopsy rejection or death. CONCLUSIONS: We report for the first time that the high level of sCD30 prior to the HTx may be associated with a higher immunologic ability of the pts and therefore, may have a protective effect in the development of infection post-Tx.

The generation and anti-myeloma activity of a chimeric anti-CD54 antibody, cUV3.

Despite new treatment options, including autologous and allogeneic stem cell transplants, multiple myeloma remains an incurable disease. The authors developed and characterized a murine anti-human ICAM-1 (CD54) monoclonal antibody, UV3, which is highly effective in SCID mice with advanced human myeloma xenografts (SCID/ARH-77). To improve the effector functions and pharmacokinetic parameters and to reduce its immunogenicity in humans, the authors engineered this monoclonal antibody into a mouse/human IgG1kappa chimeric (c) antibody, cUV3. Following coexpression and purification of the genetically spliced heavy and light chain constructs, the authors compared cUV3 and UV3 in various in vitro assays, including relative cell-binding affinities and effector functions, namely antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The authors compared their in vivo retention times and biodistribution patterns in normal mice. In each assay, the authors found that cUV3 was essentially equivalent to UV3. Finally, these antibodies were tested in a SCID/ARH-77 model of advanced myeloma, with daily treatments of 4 mug/g for 4 consecutive days commencing 14 days after tumor cell inoculation. cUV3 was at least as effective as UV3; 40% and 20% of the mice, respectively, were cured, with no sign of disease at day 150. The authors intend to evaluate the efficacy of cUV3 further in SCID/ARH-77 mice using other doses and dosing schedules to try to improve the cure rate. Eventually, they hope to test the efficacy of cUV3 in patients with multiple myeloma.

A comparison of the in vitro and in vivo activities of IgG and F(ab')2 fragments of a mixture of three monoclonal anti-Her-2 antibodies.

PURPOSE: We have demonstrated previously that a mixture of three anti-Her-2 monoclonal antibodies (MAbs) that bind to different epitopes on the extracellular domain of Her-2 expressed on a human breast cancer cell line has more potent antitumor activity than the individual MAbs both in vitro and in xenografted severe combined immunodeficient mice. Because the activity of Herceptin is Fc dependent, we determined whether this would also be the case when a mixture of these three anti-Her-2 MAbs was used. EXPERIMENTAL DESIGN: IgG and highly purified F(ab')(2) fragments of the anti-Her-2 MAbs and Herceptin were prepared and evaluated for their ability to induce cell death, inhibit vascular endothelial growth factor secretion, and mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity in vitro. They were also compared for their abilities to induce regression of large BT474 tumors in severe combined immunodeficient mice. RESULTS: All of the F(ab')(2) fragments were >95% pure and, as expected, did not mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity in vitro. The in vitro antiproliferative and proapoptotic effects of the IgGs and F(ab')(2) fragments were similar. In contrast, the IgGs had significant antitumor activity in vivo, whereas their F(ab')(2) fragments were only marginally effective even at 5-fold higher doses to offset their shorter half-lives. CONCLUSIONS: These results confirm the importance of the Fc portion of Herceptin for optimal in vivo activity and demonstrate that even a mixture of three anti-Her-2 MAbs that are highly effective at inducing cell death in vitro requires Fc-mediated effector function for optimal in vivo activity.

Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo.

Her-2 (p185(erbB-2)) is a transmembrane tyrosine kinase receptor, which is encoded by the Her-2/neu proto-oncogene. Her-2 is overexpressed on 30% of highly malignant breast cancers. Monoclonal antibodies (MAbs) against Her-2 inhibit the growth of Her-2-overexpressing tumor cells and this occurs by a variety of mechanisms. One such MAb, Herceptin (Trastuzumab), has been approved for human use. We have generated a panel of murine anti-Her-2 MAbs against nine different epitopes on the extracellular domain of Her-2 and have evaluated the antitumor activity of three of these MAbs alone and in combination, both in vitro and in vivo. We found that MAbs (against different epitopes) make a highly effective mixture, which was more effective than the individual MAbs in treating s.c. tumor nodules of BT474 cells in SCID mice. In vitro, the MAb mixture was also more effective than the single MAbs in inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, inhibiting cell growth and inducing apoptosis, and inhibiting the secretion of vascular endothelial growth factor. Taken together, these activities might explain the superior performance of the MAb mixture in vivo.